Project Summary Understanding subtypes of gastroparesis and the pathophysiology of symptoms associated with gastroparesis are required before improved treatments can be designed. Our aims are to 1) define major subtypes of gastroparesis using physiological testing for gastric myoelectrical activity (GMA), accommodation, and autonomic nervous system function and 2) explore pathophysiological mechanisms of meal-induced symptoms in patients with gastroparesis and gastroparesis-like syndromes. Variable depletion of interstitial cells of Cajal (ICCs) creates a continuum of dysfunction of electrical and contractile activities of the stomach. Physiological tests to measure gastric emptying, gastric myoelectrical activity (GMA), and gastric accommodation reflect this continuum of ICC depletion from gastric dysrhythmias and normal gastric emptying to delays in gastric emptying. Our recent observations revealed two important subtypes of gastroparesis: 1) obstructive gastroparesis and 2) gastroparesis with postural orthostatic tachycardia syndrome (POTS). Preliminary studies show positive responses to pyloric therapies and to fludrocortisone and vitamin D in these subtypes, respectively. The important physiological differences in these subgroups of gastroparesis provide the rationale for more precise, individual treatments. Physiological testing during provocative test meals in symptomatic patients with normal gastric emptying (e.g. chronic unexplained nausea and vomiting, dysmotility-like dyspepsia, or postprandial distress syndrome) unmasks subtypes with: 1) gastric dysrhythmias or normal 3 cpm GMA and 2) normal or abnormal gastric accommodation. Our studies will utilize the database of Registry 2 of the Gastroparesis Clinical Research Consortium which contains extensive physiologic data in patients with idiopathic and diabetic gastroparesis and in patients with normal gastric emptying and new data from patients enrolled in the continuation of the Registry. This project will characterize clinically important subgroups of symptomatic patients with or without gastroparesis, increase our understanding of the underlying pathophysiology of gastroparesis-associated symptoms, and lead to more rational therapies based on physiological test results.